tbuckley/cabot-search huggingface dataset:
Theory-guided assessment of barriers and facilitators to adequate informed consent for childhood cancer clinical trials: Using the Exploration, Preparation, Implementation, Sustainment (EPIS) framework.
Authors: Paula Aristizabal, Britney Vu, Bianca Perdomo, Bonnie N Kaiser, Jesse Nodora, Courtney D Thornburg, Elena Martinez, Gregory A Aarons
Journal: Journal of Clinical Oncology (2022)

6539 Background: To participate in childhood cancer clinical trials, parents/legal guardians must provide informed consent (IC), which is a fundamental ethical right. However, barriers to achieving valid IC include: use of medical jargon, misunderstanding about clinical trials procedures, tremendous emotional distress surrounding the initial cancer diagnosis, and the complexity and length of the IC forms. There are scarce data on using theory to assess perspectives of parents of children with cancer on barriers and facilitators for adequate IC in diverse populations. Methods: Using implementation science theory and methods, we assessed parent-reported barriers and facilitators to adequate IC, in a convenience sample that included a significant number of Hispanics. Twelve qualitative semi-structured interviews and 224 open-ended surveys were conducted with 236 parents of children with newly-diagnosed cancer at Rady Children’s Hospital-San Diego, a large quaternary children’s hospital in California. Fifty-three percent of participants were Hispanic and 38% were monolingual Spanish-speakers. We utilized the Exploration, Preparation, Implementation, Sustainment (EPIS) Framework, specifically domains of outer context, inner context, bridging and innovation factors. Four main codes (IC concepts and delivery; desired clinical trial information; motivations and emotions related to clinical trial enrollment; and potential areas for interventions) were used as a coding guide for analysis. Interviews and surveys were transcribed and coded for thematic analysis by three independent coders to identify key barriers and facilitators. Results: Four main themes were identified as barriers: 1) Complexity of the IC forms and discussion (lengthy, confusing, not available in Spanish, and use of medical jargon); 2) parents feeling emotionally overwhelmed, anxious and pressured around the IC; 3) parents viewing the clinical trial as the only treatment option; and 4) mistrust and fear of clinical trial procedures. Four IC facilitators were identified: 1) simpler explanations of study procedures; 2) provider flexibility for accommodations when delivering the IC, including psychosocial support; 3) active promotion of voluntariness and trust; and 4) supplemental education in lay language, including request for peer-education, decision aids, and navigation to “bridge the provider-patient gap.” Conclusions: Our implementation science approach identified multiple barriers and facilitators to adequate IC in a diverse sample of parents. Findings can inform potential interventions to enhance IC for childhood cancer clinical trials, including the use of decision aids, peer-navigation, and interventions tailored to the language and culture of the individual.
Changes in endothelial characteristics as a new strategy to identify intracranial aneurysm at risk of rupture
Authors: A Cayron, S Morel, P Bijlenga, E Allemann, B Kwak
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Background Intracranial aneurysm (IA) is an arterial disease resulting in abnormal enlargement of the vessel lumen. Most IAs are asymptomatic but their rupture induces subarachnoid hemorrhage with 24% resulting in death and 11% in severe disability. Occlusion of an unruptured IA by microsurgical or endovascular treatment results in a procedural morbidity and mortality of between 4 to 7%. Decision making between "intervention" or "continuing observation" for an individual patient is currently based on clinical scores and further supported by radiologic imaging of IA characteristics including the observation of vessel wall enhancement (VWE) on magnetic resonance imaging (MRI). VWE reflects a local accumulation of colloid contrast agent, which has been associated with IA wall instability. The pathophysiology of VWE is unknown but enhanced permeability of arterial endothelium, excessive macrophage infiltration, or presence of vasa vasorum have been proposed as potential mechanisms. Purpose The goal of our study is to investigate the expression of tight junction (TJ) proteins in the arterial endothelium of human IA domes in the context of IA wall instability. To this end, we have compared ruptured and unruptured IA domes from a human IA biobank. Methods Human aneurysms from the middle cerebral artery were obtained during microsurgery by resection of the IA dome after clipping of the neck, embedded in paraffin, and then sectioned and stained for the endothelial cell marker CD31 and the TJ proteins Claudin-5 and Zonula occludens-1 (ZO-1). The expression of these proteins was compared between ruptured and unruptured IAs. Results are expressed as a median (interquartile range). Results Histological analyses for CD31 revealed that endothelial cell coverage in ruptured (N=16) IAs tended to be decreased compared to unruptured (N=30) domes (27% (10-49) versus 38% (23-77) respectively, P=0.06). Interestingly, in ruptured aneurysms the expression of the TJ proteins Claudin-5 (1.70um (1.52-2.04)) and ZO-1 (2.29um (1.96-2.75) was lower in comparison with unruptured samples (Claudin-5: 2.15um (1.90-2.76), P&amp;lt;0.05; ZO-1: 2.66um (2.40-3.66), P&amp;lt;0.05). Conclusion Our study revealed reduced expression of Claudin-5 and ZO-1 in ruptured IAs in comparison with unruptured IA domes. Reduction in TJ proteins may lead to increased endothelial permeability thus favoring the accumulation of MRI contrast agent in the IA wall and the observation of VWE. Focusing on changes in endothelial characteristics and permeability may represent a new strategy to identify IAs at risk of rupture.
Does acute cholangitis impact outcomes of cholangiocarcinoma? Insights from a nationwide database.
Authors: Raymond Lee, Diana Franco, Umer Farooq, Asmi Chattaraj, Mohammad Ebad Ur Rehman, Faiz Anwer
Journal: Journal of Clinical Oncology (2022)

e16138 Background: Cholangiocarcinoma is a malignancy associated with poor survival and outcomes. Structural abnormalities causing bile duct obstruction frequently lead to superimposed acute cholangitis (AC). We evaluated the impact of AC on hospitalized patients with cholangiocarcinoma. Methods: We investigated National Inpatient Sample 2019, employing International Classification of Diseases-10 (ICD-10) codes to include adult patients with cholangiocarcinoma. Analyses were performed using STATA (v 14.2), considering 2 sided P&lt; 0.05 as statistically significant. Proportions were compared using Fisher exact test and continuous variables using Student’s t-test. Confounding variables were adjusted using multivariate logistic and linear regression analyses and included: gender, race, Charlson Comorbidity Index (CCI) score, median household income for patients’ zip codes, hospital location/region/ bedside, and insurance status. Results: A total of 36,900 patients were included in the analysis. Of those 15.26% (5,630) had AC on presentation (Table). Concomitant AC was associated with a higher adjusted length of stay (LOS) by 1.78 days and hospitalization cost by 3,028 USD in cholangiocarcinoma patients ( P&lt; 0.01). There were higher adjusted odds of acute renal failure (Adjusted odds ratio (aOR) 1.31, P&lt; 0.01) and lower odds of aspiration pneumonia while hospitalized in AC patients (aOR 0.37, P&lt; 0.01). ERCP represented the primary technique of biliary drainage. No disparities were seen between the two groups undergoing ERCP or cholecystostomy tube, which resulted in comparable mortality trends ( P&gt; 0.05). Rates of acute respiratory failure, mechanical ventilation, ICU admission, cardiac arrest, and sepsis were not different between the two groups ( P&gt; 0.05). Conclusions: Unbiased and comparable biliary drainage via either ERCP or cholecystostomy resulted in observing no mortality differences between the two groups. However, superimposed AC in cholangiocarcinoma patients results in higher LOS driven by acute renal failure.[Table: see text]
Adipose mesenchymal stem cells from different fat depots in obese and lean subjects have different microRNA signatures involved in their differentiation into endothelial cells
Authors: A Civit-Urgell, L Badimon, G Arderiu
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III - Fondo de Investigaciones Sanitarias (FIS) P20/01517 to GA and Spanish Ministry of Science and Innovation PID 2019-107160RB-I00 to LB. All grants were co-financed by European Union Funds, Fondo Europeo de Desarrollo Regional (FEDER) "Una manera de hacer Europa". Background/Introduction: Cell-based regenerative medicine has emerged as the forefront therapeutic procedure to improve ischemic tissue recovery. This approach is based on the usage of multilineage stem cells that can contribute to tissue regeneration. Revascularization of ischemic tissues is one of the objectives of cell therapy1,2. In this regard, we have investigated adipose-derived stem cells (ASCs), multipotent adult mesenchymal stems cells, as a cell source for therapy because of their capability to differentiate into endothelial cells (ECs)3–5. The regulatory mechanisms that drive the differentiation to EC are under investigation. Purpose Our hypothesis is that microRNAs (miRNAs) are involved in ASC to EC differentiation by a defined genetic signature in each fat tissue depot. The understanding of these mechanisms may be used to promote neovascularization in ischemic tissue. Methods Human ASCs from white adipose tissue (WAT) were obtained by surgical procedures from lean and obese patients. Importantly, subcutaneous-WAT and visceral-WAT were obtained from the same obese patient. ASCs from fat depots of lean and obese subjects where induced to differentiate into endothelial cells. The expression of 2025 pre-miRNAs and 2578 mature miRNAs was assessed using miRNA arrays in four biological replicates. Results Differentially up-regulated and down-regulated miRNAs were obtained from the respective fat depots. Seven of the most differentially expressed miRNAs were validated by qRT-PCR. The miRNA targets involved in the regulation of angiogenesis were selected by bioinformatic algorithms. We have identified 4 miRNAs that promote and stimulate ASCs differentiation into cells with endothelial cell-like phenotype through the regulation of FGFR1, NRP2, MAPK1, TGFB2, ETS1 and PTPN9. Conclusion In summary, the regulation of ASCs to EC differentiation (endotheliogenesis) involves a distinctive miRNA signature relying on WAT depot.
Outcomes of responders to PD-1/PD-L1 inhibitors who discontinue therapy after sustained disease control.
Authors: Harsh Sharma, Krishna Rekha Moturi, Emrullah Yilmaz, Olumide B. Gbolahan, Atul Kumar, Neda Hashemi-Sadraei
Journal: Journal of Clinical Oncology (2022)

2586 Background: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are widely used in the treatment of metastatic malignancies. Judiciously balancing disease control (DC) against development of immune-related adverse events (irAE) remains a crucial aspect of treatment. The effect of treatment discontinuation after sustained disease control (SDC) is unknown. The purpose of this analysis was to evaluate outcomes of responders to ICI who discontinue treatment after a minimum of 12 months (SDC). Methods: We retrospectively reviewed the database of the University of New Mexico Comprehensive Cancer Center between 2014 and 2021 and identified patients who had received ICI. Patients with metastatic solid tumors who had stopped ICI therapy after achieving SDC [stable disease, partial response, complete response (SD,PR,CR)] were selected and outcomes reviewed from their electronic health records. Results: We identified 204 patients who were treated with ICI for various solid cancers. Forty-four patients (21.6%) met the criteria, of whom 35 with follow-up data were included in the final analysis; including 11 melanoma, 5 non-small cell lung, 4 head &amp; neck, 8 renal, 4 urothelial, 1 anal, 1 Merkel cell carcinoma, and 1 liposarcoma. Patients were divided into two groups: those who stopped ICI due to an irAE [irAE group, n=14, median treatment time (MTT), 16.6 mo] and those who stopped due to other reasons (eg completion of 2 years of therapy, n=20, non-cancer related surgery, n=1) (non-irAE group, n=21, MTT, 23.7 mo). Among the irAE group, the most common irAE included pneumonitis, rash, transaminitis, and fatigue. As of data cutoff date, 10 of 14 (71%) patients continued to show SDC. Only 4 of 14 (28.6%) patients in this group experienced progression of disease (PD), one of whom was re-challenged with nivolumab and achieved DC (median follow-up of 19.2 mo after last dose of treatment, range 3-50.2 mo). Among the non-irAE group, 13 of 21 (62%) continued to have SDC. Eight of 21 (38%) experienced PD after stopping treatment, 7 of whom received ICI rechallenge, with 2 of 7 achieving DC (median follow-up of 22.2 mo, range 3.6-54.8 mo). At a median follow-up of 21.3 mo from stopping ICI therapy (range, 3-54.8 mo), 10 patients (71%) from the irAE group and 13 (61.9%) from the non-irAE group are in DC and have not experienced PD. Conclusions: We demonstrate that 23 (66%) patients experienced SDC, regardless of cancer type or development of irAE. After including patients who were re-challenged with ICI due to PD, 26 (74%) remain in DC. Future prospective malignancy-specific trials such as NCT04637594 are warranted to evaluate optimal treatment duration. [Table: see text]
Bacterial community composition in breast cancer subtypes.
Authors: Alfred Chan, Madiha Naseem, Mykola Onyshchenko, Delphine Lee
Journal: Journal of Clinical Oncology (2022)

e13063 Background: Breast cancer is a heterogeneous disease with multiple molecular subtypes and prognostic outcomes. Among these subtypes, Luminal-A is enriched with estrogen receptor and has the best clinical prognosis, whereas triple-negative breast cancer (TNBC) remains an aggressive subtype with poor prognosis. Changes in the diversity of breast microbiome have been associated with breast cancer initiation and progression. We hypothesized that Luminal-A and TNBC subtypes will have differences in both bacterial community composition as well as differences in microbial genomes and pathways. Methods: 6 Luminal-A and 6 TNBC FPPE tissue blocks were processed for both 16S V4 rRNA amplicon sequencing and shotgun metagenomics sequencing. 16S sequencing data was processed using mothur (v1.44.3) and reads were assigned taxonomy against the SILVA 16S rRNA database (v132). Shotgun sequencing was processed using the EBI-Metagenomic (v5) pipeline; bacterial identification was performed using the Kraken pipeline. Results: Shannon alpha-diversity or species enrichment, was significantly higher in Luminal-A compared to TNBC (nonparametric, P = 0.008) and their microbiome composition was significantly different by beta-diversity analysis (bray-curtis dissimilarity, PERMANOVA, P = 0.014). Bacteroides and Sphingomonadaceae species were significantly higher in abundance in Luminal-A, compared to Pseudomonas and Neisseriaceae species abundance in TNBC. Results were validated by shotgun sequencing. Luminal-A and TNBC bacterial metabolic pathways were not statistically different overall (PERMANOVA, P = 0.312). Pathways associated with Luminal-A included Response to Wounding (GO: 0009611), tRNA modification (GO: 0006400), and Cytoplasmic Microtubule Organization (GO: 0031122). Pathways associated with TNBC included troponin complex (GO: 0005861), rRNA processing (GO: 0006364), and CDC73 PAF1 (GO: 0016593). Conclusions: Using both shotgun and amplicon sequencing, this is the first analysis to show that Luminal-A and TNBC subtypes have statistically significant differences in bacterial species composition. Luminal-A had higher species diversity and abundance of Sphingomonadaceae, which are associated with healthy breast tissue and better clinical outcomes. TNBC had lower species diversity and abundance of Pseudomonas and Neisseriaceae, which have been associated with tumor survival and cell growth. Understanding the role of microbiota and its complex interaction with tumor microenvironment could help identify new treatment targets in breast cancer subtypes, and warrants further investigations.
QOL-29. Neuropsychology for you“ – tools to improve awareness of and access to neuropsychological care
Authors: Liesa Josephine Weiler-Wichtl, Verena Fohn-Erhold, Alina Kollmann, Jonathan Fries, Carina Schneider, angelika Holzer, Verena Rosenmayr, Beate Schreiber-Gollwitzer, Peggy Lüttich, Henning Ross, Thomas Pletschko, Maximilian Hopfgartner, Ulrike Leiss
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE: The occurrence of neuropsychological late effects in childhood brain tumor patients is well known in literature and practice, as well as the use of neuropsychological testing and therapy procedures. Despite guidelines, actual care is quite heterogeneous and often does not meet the needs due to lack of resources. Therefore, a standardized tool to improve awareness of and access to neuropsychological assessment, but even more treatment was developed. METHODS: The core of this Quality-Improvement project is a multilevel and interdisciplinary approach characterized by iterative processes (PDSA-cycles): (1) conceptualization by interdisciplinary, multicenter teams of experts, (2) consensus in Delphi surveys by medical, nursing and psychosocial experts (N=45) and final approval by the steering group. (3) Pilot phases (N=44): Manageability and acceptance, emotional well-being and the degree of information were recorded using a process-oriented screening. RESULTS: The expert meetings resulted in two booklets ("Look closely - Psychosocial assessment" &amp; "1,2,3 - All about Neuropsychology"): Each booklet offers creative methods with a high prompting character to motivate the child to participate actively in two face-to-face sessions (psychoeducational, work and exercise and reflection section). They enable patients to make themselves experts on these topics with age-appropriate, interactive methods. The Delphi survey revealed a consensus of 69%-93%. Patients using the Psychosocial-assessment booklet showed generally low negative emotions and stable positive emotions, which significantly increased during the second session (Z = 2.156, p = .031). Moreover, positive emotions increase significantly during the second session (Z = 2.805, p = .005). Self-indicated degree of information increases significantly with both booklets (Psychosocial assessment: Z = 3.133, p = .002; Neuropsychology: Z = 2.751, p = .006). CONCLUSION: The results illustrate a positive emotional approach to neuropsychological assessment and treatment. Likewise, the rapid increase in expert knowledge supports access to this specific topic and can be considered a minimum standard.
ATM germline variants in a young adult with chronic lymphocytic leukemia: 8 years of genomic evolution
Authors: Romina Royo, Laura Magnano, Julio Delgado, Sara Ruiz-Gil, Josep Ll. Gelpí, Holger Heyn, Malcom A. Taylor, Tatjana Stankovic, Xose S. Puente, Ferran Nadeu, Elías Campo
Journal: Blood Cancer Journal (2022)
FoRT 05-BEAT: A phase II randomized trial comparing atezolizumab versus atezolizumab + bevacizumab as first-line treatment in patients with PD-L1 high advanced/metastatic NSCLC.
Authors: Rita Migliorino, Lorenza Landi, Domenico Galetta, Daniela Soregaroli, Serena Ricciardi, Gabriele Minuti, Michele Montrone, Ilaria Marech, Alessandro Morabito, Rossana Berardi, Silvia Novello, Danilo Rocco, Sara Pilotto, Francesca Zanelli, Carmelo Bengala, Angelo Delmonte, Michele Aieta, Diego Luigi Cortinovis, Federico Cappuzzo
Journal: Journal of Clinical Oncology (2022)

TPS9145 Background: Several ongoing phase III studies are evaluating the efficacy of first-line atezolizumab in combination with chemotherapy in patients with non small-cell lung cancer (NSCLC). Among angiogenesis inhibitors, bevacizumab is approved as first-line therapy in combination with chemotherapy or in combination with erlotinib in patients with NSCLC harboring activating EGFR mutations. Recent evidence (Wallin 2016) suggests that the combination of atezolizumab and bevacizumab increases intra-tumoral CD8+T cells, suggesting that dual VEGF and PD-L1 inhibition improves antigen-specific T-cell migration. In addition, preliminary clinical data suggested a strong synergistic effects of bevacizumab with immune checkpoint inhibitors. There is therefore a strong rationale for investigating the combination of atezolizumab and bevacizumab in patients with advanced/metastatic NSCLC. The FoRT 05-BEAT is a multicenter, Italian, phase II, randomized study comparing atezolizumab monotherapy versus the combination of atezolizumab and bevacizumab in patients with chemo-naive metastatic NSCLC and high levels of PD-L1 expression. Methods: The trial was conducted in 35 Italian centers: chemotherapy naive metastatic NSCLC patients, with high levels of PD-L1 expression (PD-L1 TPS ≥50% or TC/IC 3 scoring) were randomly assigned to atezolizumab monotherapy (1200 mg every 3 weeks) or to the combination of atezolizumab (1200 mg every 3 weeks) and bevacizumab (15 mg/kg every 3 weeks).The primary endpoint is overall survival (OS) rate at 18 months. Secondary endpoints include response rate (RR), PFS, OS according to presence of bone and/or hepatic metastases. Safety considerations will be considered. Exploratory analysis of predictive biomarker on tumor tissue and blood samples has been planned. Sample size has been calculated assuming a 18 months OS of 50% in the atezolizumab arm. Therefore, a total of 186 patients is needed to detect an absolute improvement of 20%, thus obtaining a 18mOS of 70% in the combination arm, with a power of 80% at a significance level of 5%. Taking into account the percentage of patients lost-to-follow-up, the sample size has been increased by 10% (N = 206 patients, 103 per arm). At the drafting of this abstract, 57 patients have already been enrolled (47 randomized). Clinical trial information: NCT03896074.